Deficiency of macrophage-derived Dnase1L3 causes lupus-like phenotypes in mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease caused by environmental factors and loss of key proteins, including the endonuclease Dnase1L3. Dnase1L3 absence causes pediatric-onset lupus in humans, while reduced activity occurs in adult-onset SLE. The amount of Dnase1L3 that prevents lupus remains unknown. To genetically reduce Dnase1L3 levels, we developed a mouse model lacking Dnase1L3 in macrophages (conditional knockout [cKO]). Serum Dnase1L3 levels were reduced 67%, though Dnase1 activity remained constant. Homogeneous and peripheral antinuclear antibodies were detected in the sera by immunofluorescence, consistent with anti-double-stranded DNA (anti-dsDNA) antibodies. Total immunoglobulin M, total immunoglobulin G, and anti-dsDNA antibody levels increased in cKO mice with age. The cKO mice developed anti-Dnase1L3 antibodies. In contrast to global Dnase1L3-/- mice, anti-dsDNA antibodies were not elevated early in life. The cKO mice had minimal kidney pathology. Therefore, we conclude that an intermediate reduction in serum Dnase1L3 causes mild lupus phenotypes, and macrophage-derived DnaselL3 helps limit lupus.

Reducción del riesgo de constipación asociada a opioides con el uso de oxicodona/naloxona: metanálisis / Use of oxycodone/naloxone for reducing opioid-induced constipation risk: a meta-analysis

Introducción: Existe una relación directa entre el uso de opioides y la constipación, que afecta la calidad de vida de los pacientes y genera sobrecostes económicos al sistema de salud, pero opciones como la oxicodona/naloxona parecen reducir la incidencia de este efecto adverso. Métodos: Revisión sistemática y metanálisis en el escenario no oncológico, oncológico y postquirúrgico. A partir de una búsqueda en las siguientes bases de datos: PubMed, Embase, Web of Science, The Cochrane Library, Google Scholar y Open Grey, se incluyeron ensayos clínicos controlados aleatorizados con o sin comparador en población mayor de 18 años, sin límite en el tiempo de búsqueda en manuscritos con idioma en español o inglés. La evaluación de los sesgos de los estudios incluidos se realizó con la herramienta de Cochrane y para la evaluación de los efectos de las intervenciones se seleccionaron las diferencias de medias, con un modelo de efectos aleatorios. La heterogeneidad se realizó a partir del modelo de DerSimonian y Laird. Análisis de heterogeneidad y homogeneidad con la prueba Q de Cochrane que se suplementa con el estadístico I2. Resultados: Se incluyeron 18 ensayos clínicos (5934 pacientes). En la población con dolor no oncológico hubo una reducción del Bowel Function Index (BFI) en 15,84 puntos (IC 95 % −22,11 a −9,57), así como en los pacientes con dolor posquirúrgico, con reducción media de la puntuación de BFI de 9 puntos IC 95 % (−16,8 a −1,2); en el grupo de pacientes con dolor oncológico no se evidenció reducción en BFI, sino un leve aumento de 2,09 puntos (IC 95 % −5,99 a 10,17). Discusión: Se evidencian limitaciones en el soporte bibliográfico y nivel de evidencia para poder establecer recomendaciones respecto a su uso. Conclusión: La combinación oxicodona/naloxona presenta una reducción en la incidencia de constipación sin generar un impacto negativo en la calidad analgésica. (AU)

Background: There is a direct relationship between use of opioids and constipation, which affects the quality of life of patients and generates additional economic costs for the health system; but options such as oxycodone/naloxone appear to reduce the incidence of this adverse effect. Methods: On this basis, a meta-analysis was conducted in non-oncologic, oncologic, and postsurgical pain populations. It was based on a search in the following databases: PubMed, Embase, Web of Science, The Cochrane Library, Google Scholar and Open Grey, which included randomized controlled clinical trials with or without a control group, in a population older than 18 years, without any specific time frame in publication date; publications in Spanish or English were included. A bias risk assessment of the included studies was performed with the Cochrane tool; for evaluation of the effect of the intervention across different studies, mean differences were selected, with a random effects model. Heterogeneity variance was estimated with the DerSimonian and Laird method. Heterogeneity and homogeneity were measured with Cochran-Q complemented with I2 statistics.Results: Eighteen randomized clinical trials (5,934 patients) were included. In the population with non-oncologic pain, there was a reduction of the Bowel Function Index (BFI) by 15.84 points, 95 % CI (−22.11 to −9.57), as well as in the patients with post-surgical pain, with a mean reduction of the BFI score of 9 points, 95 % CI (−16.8 to −1.2); in the group of patients with oncologic pain no reduction in BFI was evidenced; instead there was a slight increase of 2.09 points, 95 % CI (−5.99 to 10.17). Discussion: There are limitations with the currently available literature and level of evidence to establish firm recommendations regarding their use. Conclusion: The oxycodone/naloxone combination presents a reduction in the incidence of constipation without generating a negative impact on analgesic quality. (AU)

Deficiency of macrophage-derived Dnase1L3 causes lupus-like phenotypes in mice.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease caused by environmental factors and loss of key proteins. One such protein is a serum endonuclease secreted by macrophages and dendritic cells, Dnase1L3. Loss of Dnase1L3 causes pediatric-onset lupus in humans is Dnase1L3. Reduction in Dnase1L3 activity occurs in adult-onset human SLE. However, the amount of Dnase1L3 necessary to prevent lupus onset, if the impact is continuous or requires a threshold, and which phenotypes are most impacted by Dnase1L3 remain unknown. To reduce Dnase1L3 protein levels, we developed a genetic mouse model with reduced Dnase1L3 activity by deleting Dnase1L3 from macrophages (cKO). Serum Dnase1L3 levels were reduced 67%, though Dnase1 activity remained constant. Sera were collected weekly from cKO and littermate controls until 50 weeks of age. Homogeneous and peripheral anti-nuclear antibodies were detected by immunofluorescence, consistent with anti-dsDNA antibodies. Total IgM, total IgG, and anti-dsDNA antibody levels increased in cKO mice with increasing age. In contrast to global Dnase1L3 -/- mice, anti-dsDNA antibodies were not elevated until 30 weeks of age. The cKO mice had minimal kidney pathology, except for deposition of immune complexes and C3. Based on these findings, we conclude that an intermediate reduction in serum Dnase1L3 causes mild lupus phenotypes. This suggest that macrophage-derived DnaselL3 is critical to limiting lupus.